The long-term goal of this proposal is to define molecular mechanisms that control synaptic strength. Synapses are dynamic-once formed, neural circuits evolve by the addition and elimination of synaptic connections and the modification of their strength. Setting and modifying the strength of synapses is important for refining developing circuits and defects in these mechanisms are a likely etiology of neurodevelopmental disorders such as autism and mental retardation. In the mature nervous system, modifying synaptic strength is important for normal processes such as memory formation and pathophysiological events such as the synaptic rearrangements underlying chronic pain or the synaptic loss in neurodegenerative disorders. To define molecular mechanisms that control synaptic strength, we are undertaking a genetic, anatomical, and electrophysiological analysis in Drosophila. Neurotransmitter is released from the presynaptic cell at specialized sites called active zones. Efficient synaptic transmission requires that active zones contain a normal complement of proteins, and that these specialized release sites be apposed to postsynaptic clusters of neurotransmitter receptor. Little is known of the molecular mechanisms that regulate the protein composition of active zones and ensure the alignment of neurotransmitter release and reception machinery. In screens for genes required for such processes, four mutants were identified in which a large proportion of glutamate receptor clusters are apparently unapposed to presynaptic release sites. These mutants will be characterized to uncover molecular mechanisms that form and maintain the active zone/receptor cluster dyad. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will improve our understanding of how nerve cells connect and communicate in the brain. If these connections do not form or function properly in a child, it may lead to neurological diseases such as mental retardation, epilepsy, and autism, while in the adult, loss of these connections may contribute to neurodegenerative disorders such as Alzheimer's disease. An understanding of the molecules that control the formation, function, and maintenance of nerve cell connections could aid in the future development of new therapies for devastating neurological diseases.